Cassette apparatus utilizing electric field for processing of blood to neutralize pathogen cells therein

ABSTRACT

An operational unit for locating and neutralizing pathogen cells in blood includes a time use cassette which has a plurality of thin holding chambers that are filled with blood drawn from a patient. A light source illuminates each of the holding chambers and passes light to an underlying sensor array such that the cells in the blood selectively block the light to produce shadow images of the cells in the sensor array. A processor performs pattern recognition to identify and locate the pathogen cells by use of an image library. After the pathogen cells are located, an electric field is activated in the cassette chamber areas that include the identified pathogen cells. Sufficient electric field energy is applied to destroy the identified pathogen cells. A pump refills the cassette holding chambers, returns the neutralized-pathogen blood to the patient, and the process is repeated for a period of time.

CROSS REFERENCE TO RELATED APPLICATIONS

Applicants have filed additional applications related to the subjectmatter of the present application. These are: Ser. No. 17/814,536 filedJul. 25, 2022; Ser. No. 17/814,537 filed Jul. 25, 2022; Ser. No.17/814,538 filed Jul. 25, 2022; Ser. No. 17/814,539 filed Jul. 25, 2022;Ser. No. 17/814,541 filed Jul. 25, 2022; Ser. No. 17/814,543 filed Jul.25, 2022; Ser. No. 17/814,545 filed Jul. 25, 2022; Ser. No. 17/814,546filed Jul. 25, 2022; Ser. No. 17/814,547 filed Jul. 25, 2022; Ser. No.17/814,548 filed Jul. 25, 2022, and Ser. No. 17/814,549 filed Jul. 25,2022.

BACKGROUND Field of the Invention

The present invention is in the field of biotechnology, semiconductortechnology and further the medical field of treating individuals whohave an infection of pathogen cells in the bloodstream.

Description of the Related Art

The presence of bacteria in human blood is a serious condition termed“bacteremia”. This condition can cause an infection that spreads throughthe bloodstream. This can also be termed “septicemia” which is definedas the invasion and persistence of pathogenic bacteria in thebloodstream. Such an infection can lead to a condition termed “sepsis”which is the body's reaction to the infection. Sepsis is a seriouscondition that can cause intense sickness including shock, and in somecases, can lead to the death of the infected person. A common pathogenicbacterium causing such infection is E. coli, but infections can also becaused by other pathogenic bacteria or organisms, such as the fungusCandida auris. The usual treatment for the patient is the application ofantibiotics to try to kill the pathogenic cells in the bloodstream.However, this treatment is not successful for many patients with abloodstream pathogen cell infection.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present invention and theadvantages thereof, reference is now made to the following descriptiontaken in conjunction with the accompanying drawings in which:

FIG. 1 is a perspective view of an overall system which includes anoperational unit and a system control unit,

FIG. 2 is a perspective view showing the interior of the enclosure 11shown in FIG. 1 ,

FIG. 3 is an elevation, section view of components inside theoperational unit shown in FIG. 1 ,

FIG. 4 is a plan view of the compression plate 51 shown in FIG. 3 ,

FIG. 5 is a bottom view of the light source shown in FIG. 3 with anarray of light generators,

FIG. 6 is an elevation, sectional view of a collimated beam lightgenerator, as shown in FIG. 5 ,

FIG. 7 is an elevation, section view of the cassette 58 shown in FIG. 3,

FIG. 8 is a bottom view of a portion of the top layer of the cassette 58shown in FIG. 7 ,

FIG. 9 is a section view along line 9-9 in FIG. 8 ,

FIG. 10 is a section view along line 10-10 in FIG. 8 ,

FIG. 11 is a partial, top view of the cassette 58 shown in FIG. 7illustrating ITO conductor lines,

FIG. 12 is a is a section view along line 12-12 of FIG. 11 illustratinga portion of the bottom layer of the cassette 58 shown in FIG. 7 ,

FIG. 13 is a view of a cassette 58 holding chamber having a plurality ofparallel ridges therein,

FIG. 14 is a partial, expanded view of conducting lines and contact padsshown in region 93 of FIG. 8 ,

FIG. 15 is a partial view layout of the electrical receiver drivers inrelation to the holding chamber,

FIG. 16 is a top view of an upper receiver,

FIG. 17 is a bottom view the upper receiver,

FIG. 18 is an expanded view of hemispherical electrical connection bumpsshown in FIG. 16 ,

FIG. 19 is a top view of a lower receiver,

FIG. 20 is a bottom view of the lower receiver,

FIG. 21 is an electrical schematic diagram for each of the upper andlower receivers,

FIG. 22 is a partial cutaway and section view of an assembled cassettewith the two layers thereof bonded together illustrating a fluid holdingchamber and corresponding upper and lower receiver drivers,

FIG. 23 is a partial, top view of a cassette illustrating two sets ofITO conduction lines,

FIG. 24 is partial, top view of the upper and lower receivers shown inrelation to a cassette fluid holding chamber,

FIG. 25 is a partial, top view of a light sensor array together withcorresponding transmitters for the upper and lower receivers,

FIG. 26 is a block diagram of a transmitter,

FIG. 27 is a partial electrical schematic diagram showing the electricalrelationship of the transmitters for the upper and lower receivers inconjunction with a local processor and sensor array on the imager andprocessor unit,

FIG. 28 is a partial, cutaway elevation view of a portion of thecassette illustrating the production of an electric field betweentransverse ITO lines,

FIG. 29 is a top-down view through the top section of the cassette shownin FIGS. 3 and 7 , illustrating blood flow channels (manifolds) into andfrom multiple holding chambers of the cassette,

FIG. 30 is a section view of a holding chamber along lines 30-30 in FIG.29 ,

FIG. 31 is a section view of a flow channel along lines 31-31 in FIG. 29,

FIG. 32 is a section view of a flow channel along lines 32-32 in FIG. 29,

FIG. 33 is an elevation view of a peristaltic pump and a portion of thecassette shown in FIG. 3 ,

FIG. 34 is a top-down view through the top layer of the cassette, shownin FIG. 3 and FIG. 29 , illustrating the flow of blood through the inputmanifold channels, holding chambers and output manifold channels,

FIG. 35 is an illustration of a pixel array integrated circuit as usedin the imaging and processing unit shown in FIG. 3 ,

FIG. 36 is an illustration of a portion of the pixel array shown in FIG.35 , showing individual pixels,

FIG. 37 is an electrical schematic of a 3T image sensor cell,

FIG. 38 is an electrical schematic of a 4T image sensor cell,

FIG. 39 is a top view of a layout of an image sensor cell,

FIG. 40 is a section view along line 40-40 in FIG. 39 of a layout of animage sensor cell,

FIG. 41 is a partial system electrical schematic,

FIGS. 42A and 42B are a light amplitude calibration logic sequence,

FIG. 43 is a top view of ITO conductor lines over a sensor array dividedinto sensor array areas for showing locations and calibration,

FIG. 44 is an illustration of longitudinal ITO lines and correspondingcalibration markers printed on a cassette for use in positioncalibration,

FIG. 45 is an illustration of an ideal and actual detected marker fortransverse position calibration,

FIG. 46 is an illustration of transverse ITO lines and correspondingcalibration markers printed on a cassette for use in positioncalibration,

FIG. 47 is an illustration of an ideal and actual detected marker fortransverse position calibration,

FIG. 48 is a set of pathogen image views for pattern recognition,

FIG. 49 is a set of red blood cell images for pattern recognition,

FIG. 50 is a set of white blood cell images for pattern recognition,

FIG. 51 is a set of platelet cell images for pattern recognition,

FIGS. 52A, 52B and 52C are a logic sequence flow of operations for adiagnostic process,

FIG. 53 is a logic sequence flow of diagnostic operations performed byeach processor to identity unique images in the pixel data,

FIG. 54 is a set of diagnostic image patterns produced in the diagnosticprocess,

FIG. 55 is a screen display of image data and counts from the diagnosticprocess described in FIGS. 52A, 52B and 52C,

FIGS. 56A, 56B, 56C and 56D are a logic flow diagram for operation of adisclosed apparatus to identify and neutralize pathogen cells,

FIG. 57 is a timing diagram for the processing operation shown in thelogic steps in FIGS. 56A, 56B, 56C and 56D,

FIG. 58 is a first set of electrical waveforms (DC) that are applied toopposing ITO lines to produce an electric field in an area of a cassettechamber,

FIG. 59 is a second set of electrical waveforms (AC) that are applied toopposing ITO lines to produce an electric field in an area of a cassettechamber,

FIG. 60 is a top-down view through the top section of a secondconfiguration of a cassette which has two arrays of holding chambers anda routing valve,

FIGS. 61A, 61B, 61C, 61D, 61E and 61F are a logic flow diagram foroperation of a disclosed apparatus having a cassette with two arrays ofholding chambers and a routing valve as shown in FIG. 60 to provide forcontinuous blood flow operation and

FIG. 62 is a timing diagram for the processing operation shown in thelogic steps in FIGS. 61A, 61B, 61C, 61D, 61E and 61F.

SUMMARY OF THE INVENTION

The present invention comprises a cassette apparatus having one or moreholding chambers for first examining blood by imaging a first quantityof blood to identify and locate pathogen cells in this quantity ofblood. The pathogen cells thus identified and located are then destroyedby the application of electric field energy to the specific locationsfor the identified and located pathogen cells. The first quantity ofblood, now processed, is then replaced in the cassette with multiplesubsequent quantities of blood and the process of identifying, locatingand neutralizing pathogen cells is repeated for each quantity of blood.After these processing operations are performed repeatedly over a periodof time, the count of viable pathogen cells in the patient blood isdecreased.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a cassette apparatus for holding blood toidentify pathogen cells in the blood of a patient and destroying theidentified pathogen cells to reduce the count of such cells in the bloodand thereby potentially reducing the harmful effect of the pathogencells to the patient.

Referring now to FIG. 1 , there is shown a system for processing bloodwhich identifies and determines locations of individual pathogen cellsin blood and then applies electric field energy to the specific locationof each located pathogen cell of sufficient magnitude to neutralize thatparticular pathogen cell. The applied energy is limited to a restrictedregion surrounding the identified pathogen cell such that nearby bloodcells, such as erythrocytes (red blood cells), leukocytes (white bloodcells) and platelets are subjected to little or no electric fieldexposure.

The principal operations performed with the blood are carried out in anoperational unit 10 which is connected by a data and control cable 12 toa system controller 14 which can be, for example, a laptop computer orcomputer work station. The operational unit 10 receives electrical powervia a power line 16.

The operational unit 10 is connected to a patient 18 by means of atwo-lumen (two fluid channels) catheter 20. In this example, thecatheter 20 is inserted into an artery in the leg of patient 18 to bothreceive blood from the patient and return blood to the patient. Thecatheter 20 has one lumen thereof connected to a blood input line 22which is connected to operational unit 10 and has a second lumenconnected to a blood return line 24 which is also connected to theoperational unit 10. The blood of patient 18 flows into the catheter 20,through input line 22 to the operational unit 10 and from theoperational unit 10 through the return line 24 and catheter 20 back tothe patient 18. A catheter, such as 20, is described in U.S. Pat. No.6,872,198 issued Mar. 25, 2005 which patent is incorporated herein byreference in its entirety.

Within the operational unit 10 the blood is imaged to identify andlocate pathogen cells in the blood followed by destroying the locatedpathogen cells. This process continues over a period of time with a flowof blood from the patient and returning processed blood to the patientwith the goal of reducing the number of viable pathogen cells in thepatient's blood.

The operational unit 10 includes an enclosure 11 having a top lid 11 awhich can be opened by use of a handle 11 b which rotates the lid 11 aon hinges 11 c. A thermal control unit 26, for example a heat pump,supplies heated or cooled air at a selected temperature through a duct27 to the interior of the enclosure 11. The thermal control unit 26 isoperated by the system controller 14 via a cable 28. The systemcontroller 14 monitors temperature inside the enclosure 11 and controlsthe thermal control unit 26 to supply air to drive the temperature inthe enclosure 11 to a preselected temperature or temperature range.

An embodiment of the cassette apparatus invention described in thefollowing text and corresponding drawings utilizes an electric field todestroy (neutralize) located pathogen cells in blood. The electric fieldis of sufficient intensity to kill the pathogen cells which have beenlocated in the blood.

The interior of the enclosure 11, shown in FIG. 1 , is illustrated inFIG. 2 . A set of four rods 30, 32, 34 and 36 are mounted on theinterior bottom surface of the enclosure 11. These rods project upward,perpendicular to the bottom surface of the enclosure 11. The top end ofeach of the rods 30, 32, 34 and 36 are threaded to receive respectivenuts 38, 40, 42 and 44. The nuts 38, 40, 42 and 44, when mounted on thecorresponding rods, engage the top surface of a compression plate 51shown in FIGS. 3 and 4 . The enclosure 11 has an opening 46 for passagetherethrough of flow tubes and electrical conductors.

An electric field system is shown in FIG. 1 , and described in thecorresponding text, with specific internal components 50 of anoperational unit 10 as shown in FIG. 3 . The operational unit 10 hasmultiple components 50 inside the enclosure 11. These components includethe compression plate 51 and a light source 54. The unit 50 furtherincludes a cassette 58 in accordance with the present invention and animager and processor unit 60. Line 22, which is flexible, extendsthrough a pump 62 to the input of the cassette 58. Pump 62 draws bloodfrom patient 18 (FIG. 1 ) through input line 22 into the operationalunit 10 and the blood leaves unit 10 through return line 24 and throughcatheter 20 back into patient 18. The components 51, 54, 58 and 60 haveplanar configurations and, in operation, are pressed together withlittle spacing between them and secured to limit relative movement. Thereturn line 24 is connected to the output port of cassette 58 and doesnot pass through the pump 62.

The compression plate 51 is shown in FIG. 4 . Plate 51 includes holes72, 74, 76 and 78 which are positioned to receive the respective rods36, 30, 32 and 36, see FIG. 2 . All of the elements 51, 54, 58 and 60are provided with colinear holes for receiving the rods 30, 32, 34 and36. When the nuts 38, 40, 42 and 44 are affixed to the rods 30, 32, 34and 36, with all of the noted components 50 (see FIG. 3 ) in place andhaving the rods 30, 32, 34 and 36 passing through each unit, the nutsare tightened on the rods to cause the compression plate 51 to applyforce to the stacked elements 51, 54, 58 and 60 to clamp them togetherand substantially limit relative movement, both horizontally andvertically, between these elements.

A planar, bottom view of the light source 54 is shown in FIG. 5 . Source54 includes a 5×6 array 68 of light generators, which includes a lightgenerator 70 which is representative of all of the light generators inthe array 68. The light source 54 produces an area of light that isdirected perpendicular to the cassette 58. Each of the light generators,including 70, produces a collimated beam of light directed perpendicularto the cassette 58. The light generator 70 is further shown in anelevation view in FIG. 6 . Light source 54 includes holes 71, 73, 75 and77 for receiving the rods 30, 32, 34 and 36.

Collimated light sources are well known in the art. Multiple embodimentsof collimated light source generators are usable with the presentinvention. A collimated light generator is described in U.S. Pat. No.7,758,208 issued Jul. 20, 2010 which patent is incorporated herein byreference in its entirety.

Referring to FIG. 6 , the light generator 70 includes a light engine 80,an extraction lens 82, a collimator lens 84, a collimator lens 86, alenslet array 88, a profile reflector 90, a secondary lenslet array 92and a secondary collimator lens 94. The light generator 70 produces acollimated beam of light 96. A collimated light source is shown in U.S.Pat. No. 7,112,916, issued Sep. 26, 2006, and which patent isincorporated by reference herein in its entirety. The light generator 70preferably produces visible light.

The cassette 58, an embodiment of the present invention, is shown in anelevation section view in FIG. 7 . Cassette 58 comprises a top layer 136and a bottom layer 138. After fabrication as separate layers, the layers136 and 138 are bonded together to form the cassette 58.

The cassette 58 has an array of holding chambers. One embodiment of thecassette 58 has an array of 30 holding chambers, as shown in FIG. 29 . Arepresentative holding chamber 86 is described in detail beginning withFIG. 8 .

Referring to FIG. 8 , there is shown a top view of a portion of thecassette 58. A holding chamber 86 position is shown as a dashed square.The chamber 86 has an input port 87 and an output port 88. An inputchannel 89 transfers blood to the input port 87 and then into thechamber 86. An output channel 90 receives blood through the output port88 from the chamber 86. A set of transverse ITO conductor lines 91extend from the bottom of the chamber 86, up a wall of the chamber 86,across a bottom surface portion of the layer 136, down a sidewall of amolded recess 92 (see also FIG. 9 ) and across a portion of the bottomof the recess 92. As shown in FIG. 9 , the ITO conductor lines 91comprise segments 91A, 91B, 91C, 91D and 91E. Segment 91A is on thebottom of the chamber 86 and extends along the full length of thechamber 86. Segment 91B is on the wall of the chamber 86, segment 91C ison the bottom surface of the top layer 136. Segment 91D is on the wallof the recess 92 and segment 91E is on the bottom of the recess 92. AnITO conductor line 97 (FIG. 8 ) extends from the bottom of recess 92, upthe sidewall to the surface of layer 136 to a pad 99. The line 97provides a common electrical connection between the upper and lowerdrivers of the cassette 58. The term ITO refers to a material made ofIndium Tin and Oxide, which material can be fabricated as a transparentelectrical conductor. ITO is well known in the semiconductor industry.

Terminations for a group of the ITO conducting lines 91 are shown in aregion 93 of FIG. 8 which is further described below.

Referring to FIG. 9 , a transparent insulating layer 95 is formed on thesurface of the ITO conducting lines 91 to insulate these conductinglines from the interior of the chamber 86, that is, when chamber 86 isfilled with blood, the ITO conducting lines 91 are electricallyinsulated from the blood. The insulating layer 95 can comprise siliconoxide, which is transparent to light. Layer 95 can be, for example, 0.25microns thick, but is not limited to only this thickness.

Referring to FIG. 10 , which is a cross-section 10-10 of FIG. 8 , thereis shown a section of the layer 136 which includes the input channel 89,the recess 92 and the output channel 90.

FIG. 11 illustrates a top view of the bottom layer 138 of the cassette58. A molded recess 98 is sized to contain a receiver that is connectedto multiple ITO conductor lines 96. An ITO conductor line 113 extendsfrom the bottom of recess 98, up the sidewall thereof, and across thesurface of layer 138 to an ITO pad 119. Pad 119 matches up and contactspad 99 (FIG. 8 ) such that the upper and lower receivers (drivers) havea common electrical terminal.

The set of light transparent longitudinal ITO conductor lines 96 areformed on the top surface of the bottom layer 138. Referring to FIG. 12, there is shown a section of the layer 138 along line 12-12 in FIG. 11. Conductor lines 96 extend from the region of the top surface of thelayer 138 under the chamber 86 (see dashed lines) into a molded recess98. Conductor lines 96 have segments 96A, 96B and 96C. Segment 96A is onthe top surface of layer 138 including under the chamber 86, segment 96Bis on the sidewall of recess 98, and segment 96C is on the bottomsurface of the recess 98.

The ITO conductor line descriptors “transverse” and “longitudinal” referto the direction of blood flow through the chamber 86. “Longitudinal”refers to a configuration parallel to the direction of flow and“transverse” refers to a direction perpendicular to the line of flow.

Referring to FIG. 12 , a transparent insulating layer 100 is formed overthe ITO conducting line segments 96A and 96B. Layer 100, like layer 95,can likewise comprise silicon dioxide.

Referring to FIG. 13 , the chamber 86 includes a plurality of parallelridges 248 which extend from the input port 87 to the output port 88.These ridges have a height equal to the thickness of the chamber 86.These ridges are further described in reference to FIGS. 29 and 30 .

FIG. 14 is an enlarged view of the region 93 shown in FIG. 8 . The ITOconductor lines 91 include individual lines 103, 104, 105 and 106. Line103 terminates at a pad 108, line 104 at a pad 109, line 105 at a pad110 and line 106 at a pad 111. Both the lines and pads comprise ITO andthe lines are electrically connected to the respective pads. The padshave a larger area than the narrow lines so that connector bumps on anintegrated circuit driver (described further below) can more easily bephysically mated for electrical contact with the individual ITOconductor lines.

The relative positioning of the chamber 86 with respect to the moldedrecesses 92 and 98 is shown in FIG. 15 . Recess 92 has mounted thereinan upper receiver (and driver) 107 and recess 98 has mounted therein alower receiver (and driver) 114. The upper receiver 107 is in the upperlayer 136 of the cassette 58 and the lower receiver 114 is in the lowerlayer 138 of the cassette 58. The receiver 107 is electrically connectedto the ITO conducting lines 91 and the receiver 114 is electricallyconnected to ITO conducting lines 96. See FIGS. 8-12 .

Referring to FIGS. 16 and 17 , the cassette 58 includes an upperreceiver 107, which is an integrated circuit, further described below,which receives a first light beam to produce electrical power and alsoreceives a second light beam which is a transmission of data. FIG. 16 isa top view of the upper receiver 107, the top surface does not have anyoptical components because the light and data transmitter projectupwards from below the receivers. A bottom view of the upper receiver107 is shown in FIG. 17 . The receiver 107 includes a light powerreceiver 117 and a light data receiver 118. Receiver 107 furtherincludes a group of electrical contact bumps 172 which includes a groupof bumps 119, which are shown in FIG. 18 . Each of the contact bumps 119has a hemispherical shape, that is, a raised center. The bumps 119contact corresponding contact pads such as 108-111 (FIG. 14 ). For oneembodiment, there are 5,000 contact bumps 172 on the bottom of the upperreceiver 107 that are positioned to respectively make separaterespective electrical contacts with 5,000 contact pads (FIGS. 8 and 9 )in the recess 92 of the upper layer 136. This electrically connects5,000 ITO lines 91 to circuitry in the upper receiver 107 such that theupper receiver 107 can selectively apply voltages to each of the ITOlines 91.

A lower receiver 114 is shown in FIGS. 19 and 20 . The upper surface ofreceiver 114 is shown in FIG. 19 . The receiver 114 has on the bottomsurface thereof (FIG. 20 ) a line of electrical contact bumps 176 whichare structurally the same as the line of contact bumps 172 on thereceiver 107 (FIG. 16 ). When the lower receiver 114 is positioned inthe recess 98 (FIG. 12 ), the line of contact bumps 176 are spaced andpositioned to respectively make individual electrical contact with theline of contact pads at the ends of lines 96 which are on the bottomsurface of the recess 98 (FIGS. 12 and 14 ). As with the suggestedembodiment, this positioning provides individual electrical connectionsbetween the lower receiver 114 and each of the 5,000 ITO lines 96. Withthis configuration, the lower receiver 114 can selectively applyvoltages to each of the ITO lines 96.

The lower receiver 114, see FIG. 20 , has on the lower surface thereof alight power receiver 112 and a light data receiver 115. The light powerreceiver 112 receives light which is converted into electrical power foroperating the lower receiver 114. Data is provided to the lower receiver114 by light transmission to the light data receiver 115.

An electrical schematic diagram of the upper receiver 107 is shown inFIG. 21 . The lower receiver 114 has the same schematic diagram. Both ofthese receivers are preferably integrated circuits. The upper receiver107 includes power receiver 117 which receives light from an LED on theprocessor unit 60 and works similarly to a solar cell to convert thelight from the LED into electrical power. Light to electrical powerconversion circuits are well known in the art. An example of a light topower conversion circuit and associated components is shown in U.S. Pat.No. 8,242,832 issued Aug. 14, 2012 which patent is incorporated byreference herein in its entirety. Alternative methods to the use oflight for transmission of power are power transmission usingelectrostatic or magnetic technology. Electrical power from the receiver117 is provided to a power controller 121 which provides voltage andcurrent regulation and control. The controller 121 is connected bybidirectional lines 132 to the power receiver 117 to provide operatingpower to receiver 117 and receive generated power from receiver 117.Power from controller 121 is sent through lines 122 and 123 to storagecapacitor 124. A power driver circuit 125 is connected to the capacitor124 by lines 122 and 123 and functions to provide electrical power vialines 126 to a multiplexor 127. The multiplexor 127 is connected to theITO lines 96 to apply selective voltages concurrently to one or more ofthe ITO lines 96. The driver 125 supplies operating power via a line 128to a processor/controller 129 and a data controller 130. Data receiver131 is coupled by lines 132 to provide data to the data controller 130and receive operating power from controller 130.

Further referring to FIG. 21 , the processor/controller 129 is coupledvia line 133 to control the driver 125, in particular to select thevoltage that is provided by the driver 125 to the multiplexor 127. Theprocessor/controller 129 is further coupled via a line 134 to controlthe multiplexor 127, in particular to select the ones of the ITO lines91 that receive the voltage supplied by the driver 125 to themultiplexor 127. In operation, data is sent to the receiver 131 which ispassed to the processor/controller 129 to define the voltages providedby the driver 125 to the multiplexor 127 and to select via line 134 theones of the ITO lines 96 that receive the voltage provided by driver 125to multiplexor 127.

Ground line conductor 97 is provided to receiver 107 and ground lineconductor 113 is provided to receiver 114. After the cassette 58 isassembled, these lines are connected together by the assembly processsuch that the receivers have a common reference voltage.

Referring to FIG. 22 , there is shown a partial section and cut-awayview illustrating the configuration of a cassette 58 chamber 86 with thetwo drivers (107 and 114) each mounted in a molded recess. Chamber 86 isa molded opening in the layer 136. The driver 107 in recess 98 iselectrically coupled via conductors 91 to within the chamber 86, at thetop of chamber 86. The driver 114 is electrically coupled to the ITOconducting lines 96 which extend into the bottom of the chamber 86. TheITO lines 91 and 96 are transverse to each other in the chamber 86 andare electrically isolated from the interior of the chamber 86 byinsulating layers 95 and 100. This is further shown in FIG. 23 whichillustrates that the ITO lines 91 and 96 are transverse to each otherwithin the chamber 86 with one set of lines at the top and the other setat the bottom of the chamber 86.

The receivers 107 and 114 are further described in reference to FIG. 24. The upper receiver 107 is an integrated circuit which includes thelight power receiver 117 and a light data receiver 118. As described inreference to FIG. 21 , the light power receiver 117 provides electricalpower for the integrated circuit receiver and driver 107 and the lightdata receiver 118 receives the data that directs the receiver 107 toapply voltages to selected ones of the ITO lines 91. The receiver 114 isan integrated circuit that includes a light power receiver 112 and alight data receiver 115. As with receiver 107, the light power receiver112 provides electrical power to the receiver 114 and the light datareceiver 115 provides data to determine which of the connected ITO lines96 have voltages applied thereto.

In FIG. 24 , the line 97 is connected to upper receiver 107 and line 113is connected to lower receiver 114. The lines 97 and 113 areelectrically coupled together so that the upper and lower receivers(drivers) 107 and 114 have a common electric terminal, such as ground.

FIG. 25 illustrates power and data transmitters that are mounted on theimager and processor unit 60. See FIG. 3 . Transmitters 139 and 141 arepositioned beside the light sensor array 137 (one of thirty such arraysin the unit 60). These transmitters direct light upward to receivers 107and 114. Transmitter 139 has a power LED transmitter 143 that sends apower light beam to the light power receiver 112 in the receiver 114 andtransmitter 139 has a data LED transmitter 145 that sends data via alight beam to the light data receiver 115 in the receiver 114.Transmitter 141 has a power LED transmitter 149 that sends a power lightbeam to the light power receiver 117 in the receiver 107 and transmitter141 has a data LED transmitter 147 that sends data via a light beam tothe light data receiver 118 in the receiver 117.

An electrical schematic diagram of the transmitter 139 is shown in FIG.26 . The transmitter 141 has the same schematic diagram as transmitter139. The transmitter 139 receives electrical power via a line 154(multiple conductors) to a power control 155. Data is provided to thetransmitter 139 via a line 156 to a data interface 157. The powercontrol 155 provides operating power via a line 159 to the datainterface 157, a processor/controller 161 and a data driver 163. Thepower control 155 further supplies driving power through a line 165 to apower driver 167. In operation, a master controller, further describedbelow, supplies data through line 156 which data is then providedthrough a line 169 to the processor/controller 161. This data specifieswhen to turn on the power LED 143 and what data is to be transmitted bythe data LED 145. The processor/controller 161, through a line 171commands the power control 155 to turn on or off the power LED 143 bythe power driver 167. Data is sent by the processor/controller 161 tothe data driver 163 via a line 170 to modulate the data LED 145 totransmit the data via the light produced by the data LED 145.

FIG. 27 is a schematic diagram which includes the transmitters 139 and141 (See FIG. 25 ). A master controller 434 is coupled to the systemcontroller 14 (FIG. 1 ) via cable 436. The master controller 434 iscoupled through a cable 437 through an I/O to multiplexor 459 and via aline 466 to a sensor array 454 (the same as the sensor array 137 in FIG.25 ) which is in turn coupled through a bus 470 to a memory 458. Thememory 458 is coupled to a processor 462 via a bus 173. The processor462 controls the transmitters 139 and 141 via respective lines 175 and177. The processor 462 receives control and data information from themaster controller 434 via a line 154. In operation, the mastercontroller 434 sends data to the processor 462 for operating thetransmitters 139 and 141. The processor 462 calculates the data to besent through the data transmitters of the transmitters 139 and 141 basedon image data received from the sensor array 454, as described ingreater detail below. The components comprising sensor array 454, memory458, processor 462 and transmitters 139 and 144 are replicated for eachsensor array in the imager and processor unit 60. See FIG. 41 whichillustrates an array of 30 sensor units.

FIG. 28 illustrates the generation of an electric field 179 byselectively applying voltages to specific ones of the ITO lines 91 and96. A section of the cassette 58 includes an ITO line 181 within thegroup of ITO lines 96 and an ITO line 183 withing the group of ITO lines91. The lines 181 and 183 are perpendicular to each other. See FIG. 28 .The upper receiver 107 can selectively apply voltages to each of the ITOlines 85, such as line 181 (FIG. 28 ) and the lower receiver 114 canselectively apply voltages to each of the ITO lines 96, such as line 183(See FIG. 28 ). For example, if a positive voltage is applied to line181 and line 183 is connected to ground, an electric field 179 isproduced between the lines 181 and 183. Because the selected individualITO lines are perpendicular to each other, the greatest magnitude of theelectric field 179 is produced in the vertical region where the linescross, as shown in field 179 in FIG. 28 . The intensity of the electricfield 179 is determined primarily by the distance between the lines atthe crossover point and the voltage difference applied between the twolines. If, for example, the separation distance is 20 microns and thevoltage difference is 40 volts, the resulting field intensity is 2×10⁶volts/meter. In an embodiment, the voltage difference can be rapidlyreversed to apply an AC electric field, at a rate of, for example, 1,000hz. The duration can, for example, range from several milliseconds tomultiple seconds, depending upon the amount of energy that needs to beapplied to kill a detected pathogen cell in the chamber 86 at thelocation of the electric field 179. Likewise, the voltage can beincreased or decreased to supply the required amount of energy. When avoltage is applied to one line of an opposed pair of ITO lines, theother line can be held at a ground, zero level.

The upper receiver 107 and lower receiver 114 have a common connection,for example ground, such that a voltage difference between opposing ITOlines produces the electric field 179. See line 97 in FIG. 8 and line113 in FIG. 11 . The pads 99 and 119 are positioned to come into contactwhen the layers 136 and 138 are bonded together to complete the commonconnection.

Further referring to FIG. 28 , multiple pairs of the ITO lines can beactivated simultaneously to produce electric fields at other locationsin the chamber 86. For example, if 500 pathogen cells are identified andlocated in the chamber 86, 500 pairs of ITO lines at those locations canbe activated simultaneously to neutralize these 500 identified pathogencells. Alternatively, groups of pairs of ITO lines can be activatedsequentially, for example, five sequences of 100 pairs of ITO lines.

The cassette 58 (see FIGS. 3 and 7 ) is shown in a top-down view in FIG.29 . The peristaltic pump 62 drives blood through input line 22 into thecassette 58 and return blood from the cassette 58 is provided throughreturn line 24. (See FIG. 1 ) The cassette 58 has a plurality of holdingchambers for the blood. An input manifold distributes the blood to theholding chambers and a return manifold receives the blood from theholding chambers and routes it to the blood return line 24. The cassette58 receives blood from input line 22 to a distribution line 140 whichsupplies blood in parallel to chamber input lines 142, 144, 146, 148,150 and 152. The blood is transferred from the chambers to chamberoutput lines 158, 160, 162, 164, 166 and 168, which lines in turn routethe blood in parallel to a collection line 180 that is connected tosupply the received blood to a return line 182 that is connected to theblood return line 24.

The cassette 58, as shown in FIG. 29 for an embodiment of the invention,has 30 holding chambers 184, 186, 188, 190, 192, 194, 196, 198, 200,202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228,230, 232, 234, 236, 238, 240 and 242. The cassette 58 input manifoldcomprises distribution line 140 and chamber input lines 142-152. Theoutput manifold comprises chamber output lines 158-168, the collectionline 180 and the return line 182. This manifold configuration providesapproximately the same blood flow path distance from the input of line140 to the output of line 182 for the blood flowing through each of theholding chambers. This configuration contributes to a more uniform flowof blood through the holding chambers and uniform pressure drop throughthe cassette 58.

Input line 142 supplies blood to each of the chambers 184, 186, 188,190, 192. Each chamber can have, for example, an X dimension of 2centimeters, a Y dimension of 2 centimeters, and a thickness (Zdimension) of 8 microns. The chamber thickness is preferably no morethan 10 microns. The facing area of each chamber is therefore 4 squarecentimeters. The opening width from the input line 142 into chamber 184is the same as the Y dimension of the chamber, in this example, 2centimeters. Likewise, the output from each chamber, such as 184, is theY dimension, in this example, 2 centimeters. A chamber, as viewed at theinput, is relatively wide (2 centimeters) and relatively thin (8microns). This configuration is the same for all of the remainingholding chambers in cassette 58. Each of the chambers has an input portand an output port. See FIG. 8 .

The blood leaves the holding chambers 186-242 and moves into thecorresponding connected chamber output lines 158-168. The exitpassageway from a chamber is the same configuration as the inputpassageway, that is, for this embodiment, the exit passageway is 2centimeters wide and 8 microns thick. The blood flows through the outputlines 158-168 into the collection line 180 and then into the return line182.

As a flow example, further referring to FIG. 29 , blood is driven intodistribution line 140 and then into chamber input line 150 and at thefar end of this line, into chamber 232. After the blood is analyzed, theblood in chamber 232 is driven out of the chamber by pump 62 into thechamber output line 166 and from the end of line 166 into the collectionline 180. From line 180, the blood flows into the return line 182 andthen into the blood return line 24. The blood travels through thecassette input manifold to all of the chambers and returns from all ofthe chambers through the cassette output manifold.

Further referring to FIG. 29 , the cassette 58 is provided withalignment holes 252, 254, 256 and 258. The cassette 58 is lowered ontothe upward facing rods 30, 32, 34 and 36 (See FIG. 2 ), mounted insidethe operational unit 10, which pass through corresponding aligned holesin the imager and processor unit 60 (See FIG. 3 ). The rods pass throughthe holes in the cassette 58 to provide alignment of the cassette 58with the imager and processor unit 60. The light source 54 (FIG. 3 ) hascorresponding alignment holes to receive the rods 30, 32, 34 and 36 sothat the imager and processor unit 60, cassette 58, and light source 54are aligned with each other. The compression plate 51 is also mounted onthe rods 38, 40, 42 and 44. FIG. 3 . The top ends of the rods arethreaded so that nuts 38, 40, 42 and 44 (See FIG. 2 ) can be applied toeach rod and tightened so that all three of these units are compressedtogether and held in alignment with each other.

FIG. 34 shows a top-down view through the top layer 136 of cassette 58.Each of the holding chambers 184-242 comprises a recessed region intothe bottom side of the top layer 136. Each chamber recess, in oneembodiment, is approximately 8 microns thick, 2 centimeters long and 2centimeters wide. Referring to FIG. 30 , each holding chamber includes aplurality of long, thin ridges 248, illustrated as horizontal lines ineach chamber in FIG. 29 , and shown in detail in FIG. 30 , which is asection view along line 30-30 of a representative holding chamber 196 inFIG. 29 . The ridges 248 are formed as a part of the upper layer 136.Example dimensions for a holding chamber and the ridges 248 are shown inFIG. 30 . The holding chamber 196 is approximately 2 centimeters wideand 2 centimeters long. The ridges 248 extend for the length (2centimeters) of the holding chamber 196, which is shown above the viewin FIG. 30 . Each ridge, in an embodiment, is preferably 8 microns highand 4 microns wide. In this described embodiment, each of the holdingchambers 184-242, has a thickness of 8 microns. In this example, thereare 20 of the elongate ridges spaced in parallel across a distance of 2centimeters. Therefore, the spacing between the ridges is approximately950 microns. Each of the ridges 248 serves as a support for the bottomlayer 138 (See FIG. 7 ) which is pressed against the top of the ridges248 shown in FIG. 30 . The ridges 248 also function as spacers tomaintain an essentially uniform 8 micron thickness over all of the areaof each holding chamber. The ridges 248, in this configuration, furtherform 21 flow channels through the chamber which reduces lateral flow ofblood and supports a straight through flow from the input port to theoutput port of each chamber.

FIG. 31 is a section view taken along lines 31-31 in FIG. 29 in thedistribution line 140. The flow channel has a flat-bottom with quarterrounded edges cross section that has been pressed or molded into the toplayer 136. The flat, and sealing, surface of the flow line 140 isprovided by the top surface of the bottom layer 138. FIG. 32 is asection view taken along lines 32-32 in FIG. 29 located in the inputline 144. It is likewise pressed or molded into the top layer 136 andcovered with the bottom layer 138. The cross-sectional area of line 144a 32-32 is substantially smaller than that of line 140 at 31-31. Thereis a greater volume of blood flow through line 14 at 31-31 than throughline 144 at 32-32.

All of the layers 136 and 138 are fabricated of, for example,transparent polycarbonate plastic, produced by a pressing or moldingprocess such as described in U.S. Pat. No. 6,998,076 issued Feb. 14,2006 which is incorporated herein by reference in its entirety. As anexample embodiment, the top layer 136 can be approximately 2-3millimeters thick, bottom layer 138 can be 1-1.5 millimeters thick for atotal cassette 58 thickness of approximately 3-4.5 millimeters. See FIG.7 .

The top layer 136 of cassette 58 can be fabricated by the use ofpolycarbonate injection molding and a metal mold. An etched glass masteris used to form the metal stamping mold. To make the glass master, theprocess starts with a sheet of glass. The sheet of glass, approximately5 millimeters thick, is sequentially masked with photoresist patterns(as done in the manufacture of semiconductors) and an acid is applied toetch the non-masked portions. The acid removes a portion of the glass,producing a recessed pattern in the glass and forming the distributionlines and holding chambers. The final 8 micron etch can be done byplasma etching to produce more vertical sidewalls on the ridges 248.After removing the last photoresist, the surface of the glass mold istreated with a mold-release component, and then is covered with a layerof nickel or silver using an electrodeless plating method. Sputteringcan be used, or a colloidal silver method can be used. Then, nickel iselectroplated over the surface to a thickness of perhaps 0.5 cm forminga metal mold. After separating the electroformed nickel mold from theglass master, the metal mold has raised areas corresponding to thedistribution lines and holding chambers. This process is similar to themanufacturing process for phonograph records, compact discs and DVDs asshown in U.S. Pat. No. 6,998,076 noted above. Heated polycarbonateinjection molding is used with the metal mold to form the recessed flowchannels and holding chambers in what will be the top layer of thecassette. The polycarbonate flows around the raised areas in the metalmold. When the metal mold and polycarbonate are cooled, thepolycarbonate sheet is removed and it has the configuration for the toplayer 136, as shown in FIGS. 29-32 . Structure can be molded into boththe top and bottom layers.

Alternately, a metal mold can be machined or etched to have theconfiguration to produce the cassette top layer 136, applying a sheet ofpolycarbonate to the mold, heating both the mold and the sheet allowsthe polycarbonate to flow into the metal mold to produce the desiredshape for the cassette 58. Further, the cassette 58 can be fabricated ofa plastic with an included anti-thrombogenic material to reduce thepossible adhering of blood that contacts surfaces of the cassette 58.Such a material is described in U.S. Pat. No. 6,127,507 issued on Oct.3, 2000, which patent is incorporated herein by reference in itsentirety. Alternatively, the anti-thrombogenic material can be appliedas a surface coating on the plastic.

FIG. 33 is an illustration of the cassette 58 and the peristaltic pump62 together with the blood flow lines. The blood input line 22 ispositioned in the pump 62 between pump rollers 62 a and 62 b and acurved pump pressure surface 66. The rollers rotate about a center shaftand compress the flexible line 22 against the surface 66. The rollersapply sufficient force to close the line 22 and, as they rotate, theyforce the blood to flow through the line 22 toward the cassette 58. Thepump can be stopped and started as needed to pump blood to the cassette58. After the blood has passed through the cassette 58, it flows throughthe return line 24 to the catheter 20 and then back to the patient 18.The structure and operation of a peristaltic pump is well known in theart, particularly in the field of kidney dialysis.

The flow of blood through the lines and chambers of the cassette 58 isshown in FIG. 34 . This is a top-down view of the layer 136 lookingthrough the transparent layer 136. Blood enters the input line 22 intodistribution line 140 and is sequentially distributed into the chamberinput lines 142-152. Note that as the volume of blood flowing throughline 140 is decreased, the size of the line 140 is correspondinglydecreased. Note that each of the distribution lines 142-152 is taperedso the line size is decreased as the amount of blood flowing in the linedecreases. For example, blood flowing in through input line 22 has aportion thereof directed into distribution line 142 and a portion ofthat flow enters holding chamber 186. As described previously, thechamber 186 is approximately 8 microns high and there are parallelridges 248 that guide the blood in a uniform flow through the chamber186. This substantially reduces transverse blood flow in a chamber. Atthe exit of chamber 186, the blood enters output line 158 where it joinsthe blood that has passed through chamber 184. The blood from thechambers 184 and 186 flows through output line 158 and is joinedsequentially by the blood from chambers 188, 190 and 192. The blood thathas flowed through the chambers 184-192 then enters the collection line180. The blood from all of the holding chambers travels into thecollection line 180 from which it flows into the cassette 58 return line182 to the blood return line 24.

Note in FIG. 34 that the configuration of flow lines and chambersprovides approximate the same travel distance for blood flowing througheach of the holding chambers 184-242. In each flow path, the blood flowsthrough or beside 10 holding chambers. For example, the blood flowthrough chamber 206 first passes chambers 184, 194 and 204 then flowsthrough chamber 206 and then passes chambers 208, 210, 212, 222, 232 and242, for a total distance of 10 chambers. This configuration contributesto uniformity of blood flow and uniformity of pressure gradientreduction for blood flow through the cassette 58.

An example light sensor array integrated circuit for use with thepresent invention is shown in FIG. 35 . A sensor array 260 includes anarray 262 of individual pixel cells, each pixel further described below.Surrounding the array 262 of pixel cells is circuitry termed control andI/O (Input and/or Output) 264 which controls the operation of the sensorarray 260 and the transfer of pixel data collected by the sensor array260. A group of data lines 266, for example 16 parallel lines, transferspixel data from the pixel array 262 to an associated memory. A set ofcontrol and power lines 268, for example 8 lines, controls the operationof the sensor array 260 and provides power for operation of the sensorarray 260 circuitry. As further described below, the sensor arrayreceives a reset signal to set an initial charge state in each of thepixels. When the pixels are exposed to light, each pixel is dischargedfrom the initial state to a final state (the pixel data) depending onthe amount of light that was received by the pixel. A command is sentthrough lines 268 which causes the sensor array 260 to transfer thecollected pixel data through one or more of the lines 266 to anassociated memory.

As an example, the pixel array 262 can have a pixel size of 0.5 micronby 0.5 micron (square configuration) and the array has a size of 2centimeters by 2 centimeters. An array of this size has 1.6×10⁹ pixelsand, if there is only one bit per pixel, either light or dark, the pixeldata is the size of the number of pixels. For a 0.25 micron by 0.25square pixel, the number of pixels in the array is 6.4×10⁹. Thesedimensions are exemplary only. Further, a sensor array larger or smallerthan array 262, as presented, may be used.

A partial section, top view of the pixel array 262 (FIG. 35 ) is shownin FIG. 36 . This illustration, for a design having dimensions listedabove, of a pixel array includes a dimension scale in microns, whichwould not be shown in an actual array, but is shown here forillustration. This top left corner of the array 262 shows individualpixels, each a square having side dimensions of 0.25 micron. A singlepixel, such as 270 (0.50 microns by 0.50 microns) is representative ofall of the pixels in the array 262.

The pixels of sensor array 260 are organized into sensor array “areas”,which are indicated by dashed lines in FIG. 36 . In this embodiment,each area is square and has dimensions of two microns by two microns.These include, for example, areas 271, 272, 273, 274, 275 and 276. Eachof these areas is below a corresponding location area in the holdingchamber in a cassette that is above the sensor array. These areas areused in the operation of the invention to locate and neutralize(destroy) pathogen cells. When a pathogen cell is identified and locatedin a specific sensor array area, the two transverse ITO lines (see FIGS.23 and 28 ) which cross above the specific sensor array area areactivated to produce an electrical field (See FIG. 28 ) at a locationwithin the holding chamber above the specific sensor area. The electricfield has sufficient energy to neutralize the pathogen cell that wasidentified and located in the specific sensor array area. This operationis further described below in reference to FIGS. 58-64 .

A circuit for each of the pixels, such as 270, in the array 260, can beany one of many types. A 3-T (three transistor) pixel circuit is shownin FIG. 37 and a 4-T (four transistor) pixel circuit is shown in FIG. 38.

Referring to FIG. 37 , a 3-T pixel circuit 300 includes a photodiode(PD) 302, a transfer transistor 306, a reset transistor 304, a drivetransistor 308 and a floating diffusion (FD) 310. A reset signal (RS) issent through a line 314 to the gate of reset transistor 304. A transfercontrol signal (TG) is provided through a line 316 to the gate oftransistor 306. The image data produced by pixel circuit 300 istransmitted through column line 312.

In operation, the pixel circuit 300 is initially reset by turningtransistor 304 (RX) on to charge node FD 310 to VDD. Next the TG signalturns on TX transistor 306 which couples the node FD to the cathode ofphotodiode 302. Upon receiving light at the photodiode 302, the diodereverse conducts and discharges node FD dependent upon the amount oflight received by the diode. The charge on node PD drives the transistor308 (DX) which applies a corresponding current to the column line 302.

A 4-T pixel circuit 326 is shown in FIG. 38 . This circuit has aphotodiode (PD) 328, a reset transistor 330 (RX), a transfer transistor332 (TX), a drive transistor 334 (DX), and a select transistor 336 (SX).A floating diffusion 338 (FD) is connected to the gate of transistor334. Transistor 330 (RX) receives a reset signal through line 342.Transistor 332 (TX) receives a drive signal (TG) through a line 344.Transistor 336 (SX) receives at its gate a select control signal (SEL)via a line 346.

The pixel data, which is the measured light, is sent through the columnlines 312 and 340 in FIGS. 37 and 38 . At the end of these lines thereis an analog to digital converter to produce a high or low, 1 or 0,digital signal. This is essentially a threshold detection. Each pixeldata represents dark or light, depending on how much light was receivedat the pixel.

Operation of the pixel circuit 326 (FIG. 38 ) begins with receipt of areset (RS) signal at transistor 330 to charge node FD 338 to VDD. Next,the transfer control signal (TG) turns on transistor 332 to couple thecathode of photodiode 328 to node FD. When the photodiode 328 receiveslight, charge is drawn from node FD to reduce the voltage on node FD,which drives the gate of transistor 334 (DX). For readout of data fromthe pixel, signal SEL is applied to turn on transistor 336 (SX) tocouple transistor 334 (DX) to the column line 340. The column line 340is sequentially used to transfer data from all of the pixels connectedto the column line.

FIGS. 39 and 40 illustrate a physical integrated circuit structure forimplementing the 4-T pixel shown in FIG. 38 . Layout 358 in FIG. 39 is atop view. A unit pixel area 362 is the area occupied by the pixelstructure. A deep trench isolation (DTI) region 364 serves to isolateeach pixel from surrounding pixels. Active area 366 is the area of thepixel which receives light. A shallow trench isolation (STI) 368separates active elements of the pixel. First border 370, second border378 and third border 380 serve to isolate elements of the pixel circuitto reduce noise. 372 is a ground element. 374 is a transfer gate. 376 isa floating diffusion. 382 is a p-well. 384 is a p-well. 386 is the drivetransistor gate. 388 is the select transistor gate and 390 is the resettransistor gate.

FIG. 40 is a section view layout 402 along line 40-40 of the structureshown in FIG. 39 . The common elements in FIGS. 39 and 40 have the samereference numerals. Element 404 is an oxide isolating layer, 405 is aborder, 406 is a polysilicon isolation layer and 410 is a photodiode inconjunction with the epitaxial layer 412. Element 414 is ananti-reflection layer. 420 is a gate isolation layer. 424 is a floatingdiffusion (FD 338 in FIG. 38 ). Light, shown by the upward pointingvertical arrows in FIG. 40 , produced by the light source (54 in FIG. 3), is transmitted to the pixel structure and in particular to thephotodiode for measuring the light received by this one pixel.

A schematic and physical structure for a light receiving pixel isdescribed in U.S. Pat. No. 9,420,209 issued Aug. 16, 2016 which isincorporated herein by reference in its entirety.

A system electrical schematic 430 for an embodiment of the invention isshown in FIG. 41 . The imager and processor unit 60 (See FIG. 3 )includes a printed circuit board 432 having multiple integrated circuitsmounted thereon. A first component is a microprocessor master controller434 having on-board memory. Master controller 434 is coupled via amulti-line cable 436 to the system controller 14. Cable 436 is includedin cable 12, see FIG. 1 . Controller 434 is connected by a control line440 to pump 62 such that the controller 434 can start and stop the pump62. The controller 434 is further connected via a line 442 to the lightsource 54 for operating the light source to selectively produce visiblecollimated light. Each of these lines can have multiple conductors forcarrying the required control signals.

An input/output multiplexer 450 is mounted on the board 432 andconnected to the master controller 434 via a multi-line bidirectionalbus 452. The bus 452 can comprise multiple printed circuit trace lines.Also mounted on board 432 is an array of sensor arrays, and two sensorarrays 454 and 456 are shown as examples for the full set of sensorarrays. The entire array has 6 columns of sensor array assemblies with 5sensor array assemblies in each column, for a total, in this embodiment,of 30 sensor array assemblies. Each sensor array is coupled to acorresponding memory, sensor array 454 is connected to a memory 458 andsensor array 456 is connected to memory 460. For each sensor array,there is also a corresponding processor, sensor array 454 has acorresponding processor 462 and sensor array 456 has a correspondingprocessor 464. Each sensor array has a bus of parallel lines connectedfrom the sensor array to the corresponding memory. For example, sensorarray 454 is connected to memory 458 through a bus 470. Sensor array 456is connected through a bus 471 to memory 460. For the entire array ofsensor array assemblies, in this embodiment, there are 30 sensor arrays,30 memories and 30 processors.

The board 432 has alignment holes 472, 474, 476 and 478 that physicallyalign with the alignment holes 252, 254, 256 and 258 of the cassette 58,see FIGS. 3 and 29 . The board 432 and cassette 58 are mounted on thefour vertical rods 30, 32, 34 and 36 (See FIG. 2 ) in the operationalunit 10 so that each of the chambers in the cassette 58 aligns with acorresponding sensor array on the board 432. Each chamber is parallel toand oriented with the corresponding sensor array.

Further in reference to FIG. 41 , viewing sensor array 454 and itscorresponding memory and processor as an example assembly, each assemblyis connected to the multiplexer 450. A control line 466 is connectedbetween the multiplexor 450 and the sensor array 454. A bidirectionalbus 468 is connected between the multiplexer 450 and the processor 462.There are likewise similar lines between the multiplexer 450 and each ofthe other sensor assemblies mounted on the board 432. The multiplexer450 can be commanded to connect the controller 434 to any one of thesensor assemblies or to multiple assemblies concurrently.

Processor 464 is connected via line 465 to the multiplexor 450. Sensorarray 456 is connected to the multiplexor 450 via a line 457. Processor462 controls and sends data to transmitter 139A via a line 463 andprocessor 462 controls and sends data to transmitter 141A via a line467. In a similar configuration, processor 464 controls and sends datato transmitter 139B via a line 469 and processor 464 controls and sendsdata to transmitter 141B via a line 473.

Further referring to FIG. 41 , in a brief description of operation, thecontroller 434 drives the pump 62 to fill the holding chambers in acassette 58 (See FIGS. 3 and 34 ) with blood. When the holding chambersare filled, the pump is stopped. The controller then sends a resetcommand to each sensor array to reset all of the pixels in each array.Next, the controller sends an activation command to all pixels in allsensor arrays. After this, the controller 434 activates the lightgenerator 54 to produce visible light for a set period of time. Whenthis time has elapsed, the controller 434 sends a control signal to allpixels in all sensor arrays to end activation. Next, the mastercontroller sends a command to each sensor array to download thecollected pixel data to the corresponding memory. After the pixel datahas been loaded in the memories, the controller 434 commands each of theprocessors mounted on board 432 to process the pixel data in thecorresponding sensor array for pattern recognition using an imagelibrary to identify and locate pathogen cells. Each processordetermines, after applying correction factors if required, the locationin the chamber for each identified pathogen cell image and determineswhich sensor array area (See FIG. 36 ) includes that location. Thecontroller 434 then downloads from all of the processors the list of allsensor areas. The processors then send to the transmitters 139 and 141for each sensor array, the list of sensor areas and these transmitterssend this data to the upper and lower receivers 107 and 114 (See FIG. 22) which activate the crossing ITO lines for these selected sensor areasand produce an electric field within each of these sensor areas, seeFIG. 28 . These electric fields neutralize (kill) the pathogen cells inthese sensor areas. Thus, selected pathogen cells in the blood,recognized from the image library, are identified, located and exposedto an electric field for sufficient time to neutralize (kill) theidentified cells. There can be hundreds or thousands of pathogen cellsidentified and neutralized in each of the holding chambers in one cycle.After the identified and located pathogen cells are neutralized, thepump 62 is started and the cassette 58 holding chambers are emptied ofprocessed blood and then filled with unprocessed blood. The pump 62 isthen stopped for the next cycle.

The processors described herein, one used with each sensor array, canbe, for example, a microcomputer, a graphic processor or a custom gatearray. The master controller can be, for example, a microcomputer or acustom gate array.

The 30 sensor arrays shown in FIG. 41 each align with a holding chamberin cassette 58 (see FIG. 29 ). There is a one-to-one relationship. Forexample, holding chamber 184 (FIG. 29 ) is positioned over and alignedwith sensor array 454 (FIG. 41 ). Each of the remaining holding chambers(FIG. 29 ) of the cassette 58 is likewise located over and aligned witha sensor array (FIG. 41 ). For each sensor array shown in FIG. 41 ,there are two transmitters located on opposite corners of the sensorarray, for example, transmitters 139A and 141A (FIG. 41 ) are located atopposite corners of the sensor array 490. An alternate configuration canposition the transmitters at the sides of the sensor array.

Operation with the cassette of the present invention can include aninitial calibration of the light energy produced from the light source54 to be sufficient to activate the individual pixels in the sensorarrays such as 454 and 456 shown in FIG. 41 . These two sensor arraysare representative of 30 sensor arrays. Also referring to FIG. 1 , asdirected by the master controller 434 after receiving an energycalibration command from the system controller 14, the energycalibration process, by operation of the controller 434, first resetsall of the pixels in all of the sensor arrays. Next, the controlleractivates all of the pixels in all of the sensor arrays and thenactivates visible light generation from the light source 54 for aselected time. The pixels in the sensor arrays are then deactivated, thepixel data transferred to the corresponding memory and the correspondingprocessor activated to run a light energy calibration routine. If thelight energy is sufficient, all of the pixels will be light, that is, nodark pixels since there is nothing in the cassette holding chambersduring this calibration process. The processor counts the number of darkpixels. The master controller 434 polls all of the processors to collectthe number of dark pixels. If the total number of dark pixels exceeds apreset threshold, such as 0.001%, the calibration process is repeatedand the selected time is incrementally increased until the number ofdark pixels is less than the preset threshold. If the initialmeasurement shows the number of dark pixels to be less than the presentthreshold, the process is repeated with shorter light activation timesuntil the threshold is crossed and the last lower value is selected asthe light activation time. The light energy can be varied by changingthe length of time the light is on, or by varying the intensity of thelight. In either case, a light activation value, either time orintensity or both, will be produced.

Light energy calibration can also be performed after the blood holdingchambers have been filled as shown by the steps in FIGS. 42A and 42B.The system controller 14 initiates the filled chambers light energycalibration by sending a command to the master controller 434. See step568 and 569. Also referring to FIGS. 33 and 34 , the controller 434drives the pump 62 to fill the holding chambers in cassette 58. See step570. Next, in step 572, the controller 434 sends a reset command to eachof the sensor arrays 480-538. After the pixels in each sensor are reset,the controller 434 commands (step 573) each sensor array to beactivated. Next, in step 74 the light source 54 is activated for aperiod of time X. The controller 434, in step 575, deactivates all ofthe sensor arrays, and in step 576 commands each sensor array todownload its pixel data to the corresponding memory. Next, in step 577,the controller commands each processor associated with a sensor array to(step 578) access the pixel data in the corresponding memory and performa light calibration process in which the number of light transitionsbetween adjacent pixels is counted. The transition can be either lightto dark or dark to light. Each pixel has four adjacent pixels and eachpossible transition is examined. For example, a dark pixel surrounded byfour light pixels produces four transitions. In step 588, the controller434 then collects the pixel transition count from each processor andadds them together to produce a total transition count corresponding tothe period of time the light generator was on. In step 589, the mastercontroller produces a table of light durations as shown below inTable 1. Next the above process is repeated with an incrementally longerperiod of time for the operation of the light generator. The number oftransitions for this period is determined and recorded. Next, inquestion step 590, it is determined if the peak value of the number oflight transitions has been passed. This is selected, for example, byhaving 100 sequential transition counts lower than a precedingtransition count. If the response to question step 590 is “NO”, in step592, the value of X is increased by a selected increment, and control isreturned to step 572. This process is repeated until a peak oftransition number is reached, as noted. If the response to question step590 is “YES”, the master controller 434, in step 594 sends the completedtable of light duration and count of pixel transitions to the systemcontroller 14. This calibration process terminates at STOP step 596. Anexample of such data is as follows. The light energy value is a relativemeasure and the Pixel Transitions number is a truncated value, such asbillions of transitions.

TABLE 1 Relative Light Energy Pixel Transitions 1 50 2 65 3 85 4 100 5120 6 140 7 150 8 165 9 160 10 150 11 135 12 125 13 115 14 105 15 90

As seen in the above Table 1 data listing, the optimum light energyvalue is “8” which corresponds to the pixel transition value “165”. Thenumber of pixel transitions is an indicator of the quantity of imageinformation present in the pixel data and is likely the best image data.Therefore, for this instance of testing, the light energy should be setto the relative level of “8” for the process described herein toidentify and locate pathogen cells in the blood. As noted above, thelight energy can be varied by time duration or by the intensity of thelight produced or a combination.

A section of pixel array 262 is shown in FIG. 43 along withcorresponding ITO lines. The array 26 includes sensor array areas 271,272, 273, 274, 275 and 276. See FIG. 36 . Each sensor area is square andhas dimensions of two microns by two microns in this embodiment.Longitudinal ITO lines 283 and 284 are within the group of ITO lines 96.Transverse ITO lines 285, 286 and 287 are within the group of ITO lines91. Note that ITO lines 283 and 285 cross over the center of sensorarray area 271. A voltage can be applied between lines 283 and 285 toproduce an electric field in a region of the holding chamber above area271. This region of the holding chamber above area 271 is between lines283 and 285. Lines 283 and 286 cross above area 272, lines 283 and 287cross above area 273, lines 284 and 285 cross above the center of area274, lines 284 and 286 cross above area 275 and lines 284 and 287 crossabove area 276. The alignment of ITO lines and areas of the pixel arrayin FIG. 43 represent correct alignment of the cassette 58, where the ITOare located, with the sensor arrays which are mounted on the imager andprocessor unit 60 which is below the cassette 58 in the operational unit10. See FIG. 3 .

When the cassette 58 is inserted into the housing 11 (See FIG. 1 ) andinstalled together with the light source 54 and the imager and processor60, all of which are secured in place by the compression plate 51, theITO lines on the cassette 58 may not be correctly aligned with thesensor arrays on the imager and processor 60. A calibration process canbe performed to collect calibration data that can be used to correct forany such misalignment. Referring to FIG. 44 , longitudinal ITO lines288, 289 and 290 are formed on the upper layer 136 of the cassette 58.Further formed on the upper layer 136 between the ITO lines, and on thesame surface of layer 136, are calibration marks 291, 292, 293 and 294.These marks are printed on the chamber surface of the cassette 58,using, for example, integrated circuit manufacturing techniques. Theshape of these marks is distinctive such that they can be easily foundin image data by pattern recognition. The longer horizontal section ofthese marks indicate that each is a mark for the longitudinal ITO lines.

Referring to FIG. 45 , there is illustrated a marker location 295 for acalibration marker on the cassette 58. If the cassette 58 with its ITOlines were positioned in the correct location, the actual image of thecassette marker would have its image at the location 295. In thisexample, the actual location is at the marker image 296. For correctalignment, marker image location should coincide with location 295. Thisoffset between location 295 and image location 296 is due tomisalignment of the cassette 58 with its corresponding sensor array. Inthis example, the transverse offset is 16 microns (71−55=16) microns onthe vertical scale) as indicated by arrow 297. Thus, when an image isdetected, the system must apply a correction factor of 16 microns inorder to select the correct ITO line that passes over the actuallocation of the detected pathogen. For example, further referring toFIG. 44 , if ITO line 290 passed over the marker location 295 for acorrectly aligned cassette 58, but if the cassette 58 is offset as shownin FIG. 45 , the system corrects for the misalignment by the 16-microncorrection factor and selects the ITO line located 16 microns upward (asshown in FIGS. 44 and 45 ) and this would indicate, in this example,that ITO line 288 is the line actually over the marker location 295. Inthis example the ITO lines are spaced four microns apart, so with anoffset of 16 microns, the correct ITO line is four lines away. Themeasurement of the offset of the actual location of the cassette 58 withrespect to its corresponding sensor array is herein termed the alignment“correction factor”.

Referring to FIGS. 46 and 47 there is shown the production of acorrection factor for the transverse ITO lines to those shown in FIGS.44 and 45 .

Transverse ITO lines 301, 303 and 305 are in the group of ITO lines 91.Alignment markers 307, 309, 311 and 313 are printed on the chambersurface of the cassette 58 along with the ITO lines 91. In FIG. 47 ,there is shown a marker actual location 315 for marker 307 and a markerimage 317 for marker 307. As described above in reference to FIGS. 44and 45 , the transverse calibration offset in FIG. 47 is 19 microns(101−82=19 microns). This correction leads to a selection of ITO 301 asbeing the actual line over the marker image 315 location, instead of,for example, ITO line 305. Thus, this is a 19-micron correction factor.For the illustrative example, a 19-micron offset corresponds to 5 ITOlines (rounded to nearest integer).

Referring to FIG. 43 , the sensor areas can be grouped into zones in thepixel array 262. For example, the array 262 can be subdivided into 16zones. The entire array (area of 4 square centimeters) has 108 areas.Each of the 16 regions has 6.25×10⁶ areas. The alignment processdescribed above can be performed for each of the 16 regions which wouldproduce alignment parameters that could be different for the differentzones due to overall nonlinear misalignment.

A pathogen cell, together with a measurement scale, is shown in multiplepositions in FIG. 48 . E. coli is a rod-shaped bacterium. The dimensionsfor this bacterium can vary but some species can be in the range of 2-3microns long and 0.25 to 1 micron thick. In FIG. 48 , there is shown inthe left column an E. coli bacterium cell 600. The left column shows anactual view of a cell and the two right columns show shadow images thatcan be produced by that view of the cell by the sensor arrays (FIG. 41). These views are based on a system as described above with 0.50 micronby 0.50-micron sensor array pixels. The cell 600 is shown at multiplerotations along a vertical axis with angles of 0, 15, 30, 45, 60, 75 and90 degrees. These multiple views are required because the cell could beat any rotation position as it is viewed in a holding chamber. The righttwo columns (a) and (b) represent possible variations on the imageproduced by the cell positioned at the indicated rotation. Images 602and 604 can be produced by cell 600 at rotation of 0 degrees. These candiffer due to edge effects and small threshold differences in pixelsensors. Images 606 and 608 could be produced for rotation 15 degrees,610 and 612 for rotation 30 degrees, 614 and 616 for 45 degrees, 618 and620 for 60 degrees, 622 and 624 for 75 degrees and 626 and 628 for 90degrees. The images 602-628 are the image library for the pathogen cell600. These images are the search targets in the pixel data foridentifying and locating the pathogen cells. These images can be locatedin the pixel data by the use of pattern recognition. Pattern recognitionfor detecting predetermined images in a digital data field is well-knowntechnology. An example patent describing such technology is U.S. Pat.No. 9,141,885 issued Sep. 22, 2015 which patent is incorporated hereinby reference in its entirety.

Referring to FIG. 49 , there are shown views of corresponding shadowimages of red blood cells, which comprise the majority of cells in humanblood. The size of red blood cells can vary, but can be in the range of6-8 microns. In FIG. 49 , left column, there is shown a red blood cell638. A red blood cell has a disc shape with a flattened center where thethickness may be 1-2 microns. Cell 638 with a rotation of 0 degrees canproduce the shadow image 640, with rotation 45 degrees the shadow image642 and with rotation of 90 degrees the shadow image 644. These imagesare included in the image library as being images to be ignored sincethey are different from the bacteria or other pathogen images that aresought.

FIG. 50 shows a white blood cell 648 having a relatively large size anda white blood cell 650 having a smaller size. These cells areessentially spherical so appear approximately the same at all rotationangles. Cell 642 can produce a shadow image 652 and cell 650 can producea shadow image 654. Again, these images 652 and 654 can be included inthe cell library as images to ignore.

A blood platelet cell 660 is shown in FIG. 51 . A platelet is a biconvexdiscoid lens-shaped) structure, 2-3 micron in greatest diameter. Thisshape is thin at the edge and thickest in the center. At a rotation of 0degrees, the cell 660 can produce a shadow image 662, at a rotation of45 degrees a shadow image 664 and at 90 degrees, a shadow image 666. Aswith the other normal blood cells, these images are used as recognitionof cells to ignore in the processing operation.

Each of the cells in FIGS. 48, 49 and 51 are shown, for illustration, ata limited number of rotation angles; but the library can contain imagesrepresenting a finer degree of rotation, for example, every 5 degrees ofrotation.

An objective of the present invention is to locate pathogen cells inblood. This is done by use of an image library which has images ofpossible pathogen cells. This library can be created from knownconfigurations of pathogen cells, such as E. coli, or by conducting adiagnostic process for a particular individual and determining whatimages for pathogen cells are present in the blood of that individual.The library can also include images of non-pathogenic cells which can beignored to enhance the speed of image recognition.

An operation that can be used in image identification is herein termed a“diagnostic process”. This can be performed to produce an image libraryto define the specific images of cells for a particular individual. Inthis process, samples of the patient's blood are scanned to determinewhat configuration of cells are present. The cell configurations thatare likely pathogen cells are then specifically targeted in theprocessing operation. By performing this initial diagnostic process, thetargeting of pathogen cells and destruction of those specific cells iscustomized for the blood of the one specific patient undergoingtreatment.

An initial aspect of the diagnostic process is defining image filterparameters to eliminate cell images that are very unlikely to bepathogen cells, such as red and white blood cells. This can reduceprocessing time. This filtering substantially reduces the volume of datathat is produced in the diagnostic process and focuses on the imagesmost likely to be pathogen cells. In addition, whether or not likelypathogen cells are identified, this information can assist in theassessment of the patient by producing specific blood cell counts.

An example set of image filter parameters, for a system having a pixelsize of 0.50 micron by 0.50 micron, are the following:

-   -   1. An image is defined as a set of at least 12 contiguous dark        pixels entirely encompassed by light pixels, but not        encompassing any light pixels.    -   2. The maximum number of dark pixels in an image is 60.    -   3. The maximum length of an image in any direction is 16 pixels.

Image pixel data, as a measured electrical quantity, typically includesnoise, and in this application, much of the noise is either a singleisolated dark pixel or a small group of contiguous dark pixels. Thisnoise can be significantly reduced by the minimum dark pixel countlimitation.

The diagnostic process is further described in reference to FIGS. 52A,52B, 52C and 53 . The diagnostic process is initiated by the systemcontroller 14 in step 680. Next, in step 682, the system controller 14downloads the instruction to perform the diagnostic process to themaster controller 434 (See FIG. 41 ) along with the number of imagecycles to perform and a list of image filter parameters, as describedabove.

The master controller 434 receives the diagnostic start command andparameters in step 684. Next, in step 686, the master controllerdownloads the diagnostic process selection and the image filterparameters to all of the processors in the imager and processor unit 60.See FIG. 41 . The master controller next starts the pump 62 in step 688and runs it for sufficient time to fill all of the chambers of thecassette 58. The master controller 434 next resets all of the pixels inall of the sensor arrays in step 690. In step 692, the master controllerwaits for the chamber fill time to expire to ensure that the chambersare filled with blood and the blood is stationary.

Next, in step 696, (FIG. 52A) the master controller activates all of thesensor arrays (FIG. 41 ) to be ready to measure incident light. Thelight source 54 is next activated, for a predetermined time, to producevisible light in step 698. After the light generation has terminated,all of the sensor arrays are deactivated in step 700 so the pixels areno longer receiving light. Next, in step 704, the master controller 434commands all of the sensor arrays to download the collected pixel datato the corresponding memories. See FIG. 41 , After the pixel data hasbeen moved to the memories, in step 706, the master controller directsall of the processors to perform the processor diagnostic operation andthereby produce diagnostic image data,

The operation of each processor to produce the diagnostic image data isdescribed in reference to FIG. 53 . In step 712, each processor receivesthe diagnostic command and the image filter parameters, see step 684 inFIG. 52A. Next, in step 714, each processor downloads the diagnosticimage data from the corresponding memory. After the diagnostic imagedata has been received, in step 716 the processor performs patternrecognition on this data, identifies images, and applies the imagefilter parameters to eliminate many of the detected images. In step 718,the processor identifies each unique image and counts the number ofoccurrences of each unique image. In step 720, the unique image shapesand number of occurrences for each image shape are transmitted to themaster controller 434. After this data transfer, the processor operationis complete for this cycle and the processor operation stops at step722.

Returning to FIG. 52A, the processor operations described in FIG. 53have been completed at step 724. At step 726, the master controllerrequests that each processor transfer the diagnostic image data to themaster controller. At step 728, the master controller 434 transfers allof the diagnostic image data received from all of the processors to thesystem controller 14. At question step 730, it is determined by themaster controller if all image cycles have been completed. If “NO”, theoperation returns to step 688 to complete another cycle. If “YES”,control goes to step 732 where the master controller 434 reportscompletion of the diagnostic process to the system controller 14, andthen proceeds to the stop step 734.

Referring to FIG. 52B, at step 736, the system controller 14 receivesall of the diagnostic image data from all of the processors. All of thisdata is examined to find each unique image and the number of occurrencesof each unique image. This is performed in step 738. It is likely thatmany of the same unique images will be received from most, if not all,of the processors. Next, the system controller sends to a display screena display of each unique image and the number of occurrences of thatimage, as set forth in step 740. The number of displayed images can bereduced by eliminating those with a low number of occurrences, forexample, a cut off at less than 1,000 occurrences.

FIG. 54 is a display of nine samples of images that could have beenproduced in the diagnostic process, a compete display could have dozensor hundreds of images. This display has images 750, 752, 754, 756, 758,760, 762, 764, and 766. See FIG. 55 for a sample display of these imageswith the corresponding occurrence counts. Although all of these imagesmeet the filter parameters, an examination of these sample imagesindicates that some may more likely represent E. coli pathogen cells(see FIG. 48 ), such as, for example, images 752, 754 and 758 and othersare less likely to be E. coli pathogen cells, such as, for example,images 764 and 756. A trained operator, or trained software such as aneural network or artificial intelligence, can study the produceddiagnostic cell images and determine which are likely to be pathogencells. This identification of candidate images is received by the systemcontroller 14 in step 742. (FIG. 52C). This selection of images isstored as a pathogen image library in step 744 and associated with theparticular individual whose blood was analyzed. The system controller 14completes its operations at step 746.

A screen display of the identified images with image counts is shown inFIG. 55 . Images with low counts or clearly non-pathogen shapes can beeliminated from consideration for use in a pathogen library that isderived from the blood of a single person.

One processing operation for neutralizing pathogen cells in blood inaccordance with the present invention is described in FIGS. 56A, 56B,56C and 56D (logic operations) and FIGS. 57, 58 and 59 (timing diagrams)utilizing the apparatus described above. This operation uses thecassette 58 configuration shown in FIG. 34 . In this cassette, bloodflows through the input port to all of the chambers in the cassette 58.Referring to FIG. 56A, the operation begins with the system controller14 at step 770. The next operation is to download the processingparameters from the system controller to the master controller 434 (FIG.41 ). An example set of processing parameters are:

-   -   1. Overall processing time. (Example: 2-10 hours)    -   2. Light generation duration. (Example: 0.1 sec to 2.0 sec)    -   3. Pixel light collection time. (Example: 0.1 sec to 0.5 sec)    -   4. Electric field generation waveforms and time durations.    -   5. Alignment data for each sensor array.    -   6. Pathogen image library.    -   7. Cassette fill time. (Example: 2-10 sec)

The processing parameters are downloaded from the system controller 14to the master controller at step 772. These parameters are received bythe master controller 434 at step 774. The master controller thendownloads certain processing parameters to the processors, such as the30 processors shown in FIG. 41 . This is step 776. These parameters are:

-   -   1. Electric field generation waveforms and time durations    -   2. Pathogen image library    -   3. Sensor array alignment data for each corresponding processor.    -   The alignment data will likely vary between processors.

After the master controller 434 has downloaded the processor data, itstarts the pump 62 (FIG. 33 ) at step 778. This action is also shown inwaveform 779 in FIG. 57 . The high level is pump “on”. The pump 62 isrun (step 780) for the cassette fill time, step 782 such that all of thechambers of the cassette 58 are filled. When the cassette 58 chambersare filled, the pump 62 is stopped. See step 782 and waveform 779.

Next, the master controller 434 resets all of the pixels in the sensorarrays. See sensor arrays in FIG. 41 , step 784 in FIG. 56B and waveform785 in FIG. 57 . After the pixels are reset, the light source 54 isactivated at step 786, preferably using a calibrated value, as describedabove. See also waveform 787 in FIG. 57 . While the light source 54 ison, the pixels in the sensor arrays are activated to collect light whichhas passed through each of the cassette chambers. See step 788 andwaveform 789.

After the sensor activation time has ended, the master controllercommands each of the sensor arrays to send the collected pixel data tothe corresponding memory, as shown in FIG. 41 . This is step 800 in FIG.56B and waveform 801 in FIG. 57 . Next, the master controller 434commands all of the processors to perform pattern recognition and imagesensor area location for the pixel data in the corresponding memoryusing the downloaded pathogen image library. And, to produce ITO linelistings for the sensor array areas where pathogen cells had beenidentified. This is done in step 802 in FIG. 56B and waveform 803 inFIG. 57 . These operations are performed by the processors in step 804.(FIG. 56C) Each of the processors detects pathogen cells by patternrecognition and identifies the sensor array area in which the identifiedcell is located. Each processor references a stored table to determinethe number of the ITO line associated with the identified sensor arrayarea. Each processor prepares an ITO line list for the correspondingupper receiver driver and lower receiver driver. See FIG. 41 .

The ITO line listings generated by each processor are transmitted to thecorresponding upper and lower receivers in steps 806 and 808 along withthe electric field waveforms that the receivers are to apply to the ITOlines. The processor sends activation commands to the receivers to startconcurrent generation of the electric field waveforms at step 809. Seewaveform 813. A first set of electric waveforms for application to theITO lines are waveforms 810 and 812 shown in FIG. 58 and alternatingwaveforms 814 and 816 shown in FIG. 59 . In FIG. 58 , the waveform 810can be applied to the selected longitudinal ITO lines by the upperreceiver (see 107 in FIG. 21 ) while concurrently the waveform 812 isapplied by the lower receiver (see 114 in FIG. 22 ). This is theapplication of a DC voltage between transverse ITO lines in which oneline is at the top of the cassette 58 chamber and the other is at thebottom of the cassette chamber. See FIG. 22 . The voltage differenceamplitude is made sufficient to neutralize the corresponding detectedpathogen cell located at the intersection of the two ITO lines.Alternatively, an AC waveform can be applied to generate an electricfield in the cassette chamber, as shown in FIG. 59 . The upper receiver,such as 107 generates waveform 814 and concurrently the lower receiver114 generates the waveform 816. The amplitude and duration of thiswaveform is made sufficient to neutralize the pathogen cell in thecassette chamber at the intersection of the ITO lines. The applicationtiming of the voltages to the ITO lines is shown in waveform 813 in FIG.57 . The processor sends the waveform activation commands to thereceivers at essentially the same time so that the waveforms aresynchronized as shown in FIGS. 58 and 59 . After sending the activationcommands, each of the processors sends a list of the identified pathogencells and the numbers of such cells found to the master controller instep 818. The act of generating the electric fields by the receivers isperformed in step 820 in FIG. 56 .

At question step 822, it is determined if the driving of the ITO linesby the receivers has been finished. Each processor can indicate to themaster controller when the activation command was sent to the receiversand the duration of the activation is known at the master controller. Ifthe activation has not been completed, the NO exit is taken to a timedelay step 823. This time delay can be, for example, 20-100milliseconds. When the response at step 822 is YES, a further inquiry ismade to determine is the processing time has been completed. This isstep 824 in FIG. 56 . This overall processing time can be for multiplehours. If the processing time is not completed, the NO exit is taken andthe above operations are repeated, beginning at step 778. (See FIG. 56A)This step starts the pump and the next steps run the pump to remove theblood that has been processed and fill the cassette 58 with unprocessedblood for repeating the complete cycle. See cycle in FIG. 57 .

If the response to question step 824 is YES, meaning that the overallprocessing time has been completed, the master controller 434, at step826, sends a processing completion report to the system controller 14with a composite (all processors) listing of the identified pathogencells and number of such cells that have been neutralized. At step 828the system controller 14 receives the processing completion report anddisplays results. The overall operation ends at step 830.

An alternate termination of the processing to the use of the “Processingtime” in step 824 is the use of Processed Pathogen Cell Count (PPCC)that is determined by the master controller in step 826. A predeterminedProcessed Pathogen Cell Count value is included in the set of processingparameter listed above in step 772 in FIG. 56A. With this alternatetermination, the question in step 824 is “Has the predeterminedProcessed Pathogen Cell Count value been reached?” If the answer is“NO”, the processing is continued at step 778 in FIG. 56A. If the answeris “YES”, the processing is concluded at step 826 in FIG. 56D.

The processing operation described above in reference to FIGS. 56A-56Dand 57 starts the pump 62 to fill the holding chambers and stops to makethe blood in the chambers stationary for examination and exposure tokill the identified pathogen cells. An alternative cassetteconfiguration and operation are described in reference to FIGS. 60, 61A,61B, 61C, 61D, 61E, 61F and 62 . In this configuration, the pump 62 runscontinuously and the blood flow is continuous. This configuration uses asecond design for a cassette in accordance with the present invention.This is cassette 850 shown in FIG. 60 . Cassette 850 has 30 chambers,the same number as in cassette 58 described above. However, in cassette850 the 30 chambers are divided into groups A and B, which are filledand processed alternately so the blood flow can be continuous and onegroup can be processing while the other group is filling. For thecassette 850, the light source 54 can be divided into two adjacent lightsources, one over the group A chambers and one over the group Bchambers.

Referring to FIG. 60 , the cassette 850 works with a valve 852 which iselectrically controlled through a line 854 connected to the mastercontroller 434. The valve 852 has its input connected to blood inputline 22 and the valve has two output lines which are input lines 856 and858 to the cassette 850. The valve has two states which are selectivelyset by signals provided through the line 854. In one state the inputline 22 provides blood to cassette input line 856, but not to line 858,and in the second state, the valve routes blood from input line 22 tothe cassette 850 input line 858, but not to input line 856.

The cassette 850 has 30 holding chambers, each chamber having the samesize and configuration for the chambers described above for cassette 58.The cassette 850 has a first set of holding chambers 860, 862, 864, 866,868, 870, 872, 874, 876, 878, 880, 882, 884, 886, and 888. These aretermed the group A holding chambers. The cassette 850 further has asecond set of holding chambers 890, 892, 894, 896, 898, 900, 902, 904,906, 908, 910, 912, 914, 916, and 918. These are termed the group Bholding chambers.

Further referring to FIG. 60 , input line 856 supplies the flow of bloodto a distribution line 920 which in turn supplies blood to input lines922, 924, and 926. Input line 922 supplies blood to chambers 860, 862,864, 866 and 868. Input line 924 supplies blood to chambers 870, 872,874, 876, and 878. Input line 926 supplies blood to chambers 880, 882,884, 886, and 888. Input line 858 supplies blood to distribution line928 which in turn provides blood to input lines 930, 932, and 934. Inputline 930 provides blood to the holding chambers 890, 892, 894, 896 and898. Input line 932 provides blood to the holding chambers 900, 902,904, 906 and 908. Input line 934 provides blood to the holding chambers910, 912, 914, 916 and 918.

Output line 936 receives blood leaving the chambers 860, 862, 864, 866and 868 and supplies this blood to collection line 948. Output line 938receives blood leaving the chambers 870, 872, 874, 876, and 878 andsupplies this blood to collection line 948. Output line 940 receivesblood leaving the chambers 880, 882, 884, 886, and 888 and supplies thisblood to the collection line 948. Output line 942 receives blood leavingthe chambers 890, 892, 894, 896 and 898 and supplies this blood to thecollection line 948. Output line 944 receives blood leaving the chambers900, 902, 904, 906 and 908 and supplies this blood to the collectionline 948. Output line 946 receives blood leaving the chambers 910, 912,914, 916 and 918 and supplies this blood to the collection line 948.

In the cassette 850, the collection line 948 is connected to a returnline 950 which is in turn connected to the blood return line 24. Theblood supplied by the pump 62 through line 22 is alternately routed bythe valve 852 to either the group A chambers or to the group B chambers.By switching the valve between its two positions, the cassette 850 isprovided with a continuous flow of blood.

The lines 920, 922, 924 and 926 comprise an input manifold for the groupA chambers of cassette 850. The lines 928, 930, 932 and 934 comprise theinput manifold for the group B chambers of cassette 850. The lines 936,938, 940, 942, 944, 946, 948 and 950 comprise the output manifold forcassette 850.

A further processing operation for neutralizing pathogen cells in bloodin accordance with the present invention is described in FIGS. 61A, 61B,61C, 61D, 61E, 61F (logic operations) and 62 (timing diagram) utilizingthe cassette 850 configuration described above. The process described inreference to FIGS. 56A, 56B, and 56C operates by filling the cassette 58with blood then stopping the pump and performing the cell imaging andprocessing. The process described in reference to FIGS. 61A, 61B, 61C,61D, 61E, 61F and 62 operates with a continuous flow of blood into thecassette 850. The chambers in the cassette 850 are divided into Group Aand Group B. While the chambers in one group are being filled, the bloodin the other group is being processed. When the blood flow to a group isswitched, processing and filling are switched. As a result, the flow ofblood from the pump 62 is continuous.

Referring to FIGS. 61A, 61B, 61C 61D and 61E, the processing is startedat step 958 in the system controller 14. Next, the system controller 14downloads processing parameters, step 960, to the master controller. SeeFIG. 41 . The processing parameters include:

-   -   1. Overall processing time. (Example: 2-10 hours)    -   2. Cycle time. (Example: 8-30 seconds)    -   3. Light generation duration. (Example: 0.10-2.0 sec)    -   4. Pixel light collection time. (Example: 0.01 sec-0.50 sec)    -   5. Electric field generation waveforms and time durations.    -   6. Alignment data for each sensor array.    -   7. Pathogen image library.

The master controller 434, in step 962 receives the processingparameters from the system controller 14. In step 964 the mastercontroller 434 downloads certain ones of the processing parameters tothe processors. These parameters include:

-   -   1. Electric field generation waveforms and time durations    -   2. Alignment data for each sensor array    -   3. Pathogen image library        The alignment data will likely be unique for each processor for        its corresponding sensor array and cassette chamber.

The master controller 434 starts the pump 62 at step 966. Next themaster controller sets the cassette valve 852 (see FIG. 60 ) at step 968to supply blood to the Group A chambers only. The pump runs for asufficient time, such as one cycle time, to fill the Group A chambers.This is a one-time start-up operation. Next, the master controller 434,at step 970, sets valve 852 to supply blood to the Group B chambers.This operation is shown in FIG. 62 in waveforms 971 and 972 at the startwhere Group B is flowing (high level on the waveform 972 and Group A isnot flowing (low level on waveform 971).

At step 974, the master controller 434 starts a half cycle timer, whichis a clock that runs for one half cycle and then generates an endsignal. Next, the master controller resets all of the pixels in theGroup A sensor arrays, step 976. See waveform 977 in FIG. 62 . The lightsource 54 (see FIG. 3 ) is activated by the master controller 434 instep 978. Also, see waveform 979 in FIG. 62 . While the light source 54is activated, the Group A sensor arrays are activated for pixel lightcollection. See step 980 and waveform 981. After the light collectiontime has expired, the master controller 434 directs each of the Group Asensor arrays to transfer the collected pixel data to the correspondingmemory. See step 982 in FIG. 61 and waveform 983 in FIG. 62 .

After the pixel data has been transferred to the memories, the mastercontroller, in step 984, commands each processor in Group A to performpattern recognition with the pixel data in the corresponding memoryusing the pathogen image library to identify pathogen cells and toidentify the sensor array area for each identified pathogen cell. Usingthis data, each processor generates an ITO line listing corresponding tothe identified sensor array areas in which pathogen cells have beenlocated. These are the ITO lines that pass over the identified sensorarray areas. See FIG. 43 . These operations are performed in step 986.See also waveform 985 in FIG. 62 .

In step 988, each processor sends an upper ITO line listing and anelectric field generation waveform and duration to its correspondingupper receiver. See FIG. 41 and waveform 989 (FIG. 62 ). In step 990each processor sends a lower ITO line listing and an electric fieldgeneration waveform and duration to its corresponding lower receiver.See FIG. 42 . After the ITO line listings have been sent to the upperand lower receivers, each processor sends essentially concurrentactivation commands to the upper and lower receivers, step 992 (FIG. 62) and waveform 993 (FIG. 62 ). These activation commands start thegeneration of the electric field generation waveforms on the specifiedITO lines, which causes electric fields to be generated in the cassettechambers at the location of identified pathogen cells. See FIGS. 58 and59 .

After the processors have completed sending the activation commands, theprocessors send to the master controller 434, at step 994 a listing ofthe identified pathogen cells and the number of such cells identified.

At step 996 in FIG. 61C, the receivers perform the generation of theelectrical waveforms that are applied to the identified upper and lowerITO lines to generate the electric fields in the cassette chambers atthe locations of the pathogen cells so that the electric fieldsneutralize the located pathogen cells.

Next, in time sequence, the master controller 434, at question step 998inquiries to determine if the half cycle timer has expired. If theanswer is NO, there is a time delay at step 1000 and then a return tostep 998. The time delay is cycled until the half cycle timer hasexpired and the answer is YES.

After the expiration of the half cycle timer, at step 1002, the mastercontroller sets the cassette valve 852 so that blood is supplied to theGroup A chambers of the cassette 850 (see FIG. 60 ). This switchterminates supplying blood the Group B chambers. See time t15 in FIG. 62. The pump continues to run.

After the valve 852 is switched in step 1002, the master controllerstarts the half cycle timer at step 1004. Next, in step 1006, the mastercontroller 434 resets all of the pixels in the Group B sensor arrays.Also, see waveform 1007 in FIG. 62 . Next, the light source 54 is turnedon for the light activation time in step 1008. See also waveform 1009 inFIG. 62 . During the light activation, the Group B sensor arrays areactivated for the pixel collection. See step 1010 in FIG. 61 andwaveform 1011 in FIG. 62 . After the pixel light collection time hasexpired, in step 1012, the master controller directs each sensor arrayto download its pixel data to the corresponding memory. See alsowaveform 1013 in FIG. 62 .

After pixel data has been transferred to the corresponding memories, themaster controller 434, in step 1014, commands each of the Group Bprocessors to perform pattern recognition to find pathogen cell imagesin the pixel data, locate the identified pathogen cells in sensor arrayareas and generate ITO lists corresponding to the sensor array areas.These operations are carried out by the processors in step 1016 of FIG.61 and as shown in waveform 1017 in FIG. 62 .

In steps 1018 and 1020 the processors send the upper and lower ITO listsand electric field generation waveforms to the upper and lower receivers(See FIG. 41 ) and waveform 1019 in FIG. 62 . The processors sendactivation commands, as previously described, essentially concurrentlyto the upper and lower receivers. At step 1024, the processors sendlistings of the identified pathogen cells and numbers of identificationsto the master controller. In step 1026, and waveform 1027, the receiversgenerate the voltage waveforms on the opposing ITO lines to produceelectric fields in the identified sensor array areas that containidentified pathogen cells.

In question step 1028, see FIG. 61 , an inquiry is made to determine ifthe half cycle timer has expired. If the answer is NO, step 1030 timedelay is performed and control is cycled back to question 1028. Thiscycling continues until the answer to question step 1028 is YES. Next isquestion step 1031 to determine if the overall processing time hasexpired. If the answer is NO, control is transferred to step 1032 inwhich the valve 852 is set to direct blood into the Group B chambers ofcassette 850 and control is then transferred to step 974 of FIG. 61 torepeat the described process until the answer to question step 1031 isYES. When this occurs, the overall processing has been completed. Next,at step 1034, the master controller stops the pump 62. Next, the mastercontroller sends, at step 1036 a processing complete report to thesystem controller 14, the report including a composite listing of thetypes and numbers of pathogen cells identified and neutralized.

At step 1038, the system controller 14 receives the processing completereport and displays the results on a user screen, or sends theinformation to a data collection center. Next, the processing isterminated at the END step 1040.

The alternate processing termination using the Processed Pathogen CellCount can likewise be used in the described process of operation forcassette 850.

After a treatment process has been completed with a patient, thecassette 58 or 850 used in the treatment is preferably removed from theunit, disposed of and a new cassette 58 or 850 installed in theoperational unit 10 (FIG. 1 ) for use with the next patient.

One cassette embodiment described above has 30 chambers in a singlecassette with a sensor, a chamber processor and memory for each chamber.However, embodiments can be implemented having different configurationswhich operate as described above. Further, the embodiments can be scaledby the number of chambers and/or flow rate through a chamber and/or dataprocessing speed to provide a desired overall flow rate for bloodprocessing. Non-limiting example embodiments are as follows:

-   -   1. 10 chambers each 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor with a single processor and memory        serving all 10 chambers.    -   2. 10 chambers each 4.0 cm×4.0 cm, each chamber having a        corresponding light sensor, processor and memory.    -   3. 30 chambers 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor, and a single processor and memory        serving all 30 chambers.    -   4. 30 chambers divided into a separate 15 chamber Group A and 15        chamber Group B with a sensor for each chamber and a single        processor and single memory for each group.    -   5. 40 chambers each 2.0 cm×2.0 cm and each chamber having a        corresponding light sensor, and a processor and memory for each        set of 10 chambers.    -   6. 100 chambers 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor, processor and memory.    -   7. 100 chambers 2.0 cm×2.0 cm, each chamber having a        corresponding light sensor and having one memory and one        processor for each 10 chambers.

Although several embodiments of the invention have been illustrated inthe accompanying drawings and described in the foregoing DetailedDescription, it will be understood that the invention is not limited tothe embodiments disclosed but is capable of numerous rearrangements,modifications and substitutions without departing from the scope of theinvention.

What is claimed is:
 1. A cassette for use in the processing of blood,comprising: a plurality of chambers within said cassette, each saidchamber having an input port and an output port, said cassette having aninput port and an output port for said blood, a distribution manifoldhaving an input coupled to said cassette input port and a plurality ofoutputs coupled respectively to the input ports of said chambers, acollection manifold having a plurality of inputs coupled respectively tothe output ports of said chambers and an output coupled to said cassetteoutput port, each said chamber having a first plurality of parallel,transparent electrically conductive lines which are electricallyinsulated from the interior of the respective chamber, each said chamberhaving a second plurality of parallel, transparent electricallyconductive lines which are electrically insulated from the interior ofthe respective chamber, said first plurality of conductive lines andsaid second plurality of conductive lines positioned on opposite sidesin each said chamber, said first plurality of conductive linespositioned perpendicular to said second plurality of said secondplurality of conductive lines in each said chamber, and an electricdriver circuit coupled to each of said first and second pluralities ofsaid electrically conductive lines.
 2. A cassette as recited in claim 1wherein each of said chambers has parallel, planar, transparent,opposing walls.
 3. A cassette as recited in claim 2 wherein the opposingwalls for each chamber have inner surfaces which are spaced no more than10 microns apart.
 4. A cassette as recited in claim 2 wherein each saidchamber includes a plurality of parallel ridges extending in length fromproximate the chamber input port to proximate the chamber output port,said ridges together with said opposing walls in each said chamberforming a plurality of parallel flow paths in the chamber.
 5. A cassetteas recited in claim 1 wherein each said chamber is a portion of arespective rectangular cross section flow channel.
 6. A cassette asrecited in claim 1 wherein said cassette comprises first and secondlayers, said first layer formed to have openings for said chambers andsaid manifolds molded therein and said second layer having a flatsurface which forms a closing wall for said openings of said chambersand said manifolds.
 7. A cassette as recited in claim 1 wherein saidcassette is fabricated of a plastic which includes a bloodanti-thrombogenic component.
 8. A cassette for use in the processing ofblood, comprising: a plurality of chambers within said cassette, eachsaid chamber having an input port and an output port, each said chamberhaving first and second parallel opposed transparent walls, saidcassette having an input port and an output port, a distributionmanifold having an input coupled to said cassette input port and aplurality of outputs coupled respectively to the input ports of saidchambers, a collection manifold having a plurality of inputs coupledrespectively to the output ports of said chambers, and having an outputcoupled to said cassette output port, a first plurality of parallel,transparent, electrically conductive lines positioned on each of saidfirst of said walls for each of said chambers, a second plurality ofparallel, transparent, electrically conductive lines positioned on eachof said second of said walls for each of said chambers, each saidchamber having an electrical insulating layer between the firstplurality of electrically conductive lines and the interior of therespective chamber and a second electrical insulating layer between thesecond plurality of electrically conductive lines and the interior ofthe respective chamber, for each of said chambers, the first pluralityof respective conductive lines are positioned perpendicular to thesecond plurality of respective conductive lines, each said chamberhaving a first driver circuit electrically connected to the firstplurality of conductive lines for the corresponding chamber, and eachsaid chamber having a second driver circuit electrically connected tothe second plurality of conductive lines for the corresponding chamber.9. A cassette as recited in claim 8 including within said cassette foreach said driver circuit a respective power providing circuit whichreceives light and generates electric power therefrom, each said powerproviding circuit electrically coupled to a respective driver circuit.10. A cassette as recited in claim 8 wherein the opposing walls for eachchamber have inner surfaces which are spaced no more than 10 micronsapart.
 11. A cassette as recited in claim 8 wherein each said chamberincludes a plurality of parallel ridges extending in length fromproximate the chamber input port to proximate the chamber output port,said ridges together with the said opposing walls forming a plurality ofparallel flow paths in the corresponding chamber.
 12. A cassette asrecited in claim 8 wherein each said chamber is a portion of arespective flow channel having a rectangular cross section.
 13. Acassette as recited in claim 8 wherein said cassette comprises first andsecond layers, said first layer formed to have openings for saidchambers and said manifolds molded therein and said second layer havinga flat surface which forms a closing wall for the openings of saidchambers and said manifolds.
 14. A cassette as recited in claim 8wherein said cassette is fabricated of a plastic which includes a bloodanti-thrombogenic component.
 15. A cassette as recited in claim 8wherein said electrically conductive lines comprise indium tin oxide(ITO).
 16. A cassette for use in the processing of blood, comprising: anarray of chambers within said cassette, each chamber having first andsecond opposed transparent walls, each said chamber having an input porttherethrough into the corresponding chamber, and each said chamberhaving an output port therethrough from the interior of thecorresponding chamber, said cassette having an input port and an outputport, a distribution manifold having an input coupled to said cassetteinput port and a plurality of outputs coupled respectively to the inputports of said chambers, a collection manifold having a plurality ofinputs coupled respectively to the output ports of said chambers, andhaving an output coupled to said cassette output port, a first pluralityof parallel, transparent, electrically conductive lines positioned oneach of said first of said walls for each of said chambers, a secondplurality of parallel, transparent, electrically conductive linespositioned on each of said second of said walls for each of saidchambers, each said chamber having a first electrical insulating layerbetween the first plurality of electrically conductive lines and theinterior of the respective chamber, each said chamber having a secondelectrical insulating layer between the second plurality of electricallyconductive lines and the interior of the respective chamber, for each ofsaid chambers, the first plurality of conductive lines are positionedperpendicular to the second plurality of conductive lines, each saidchamber having a respective first driver circuit coupled to the firstplurality of conductive lines for the corresponding chamber, and eachsaid chamber having a respective second driver circuit coupled to thefirst plurality of conductive lines for the corresponding chamber.
 17. Acassette as recited in claim 16 wherein said conductive lines compriseindium tin oxide (ITO).
 18. A cassette as recited in claim 16 whereinsaid opposing transparent walls have inner surfaces which are spaced nomore than 10 microns apart.
 19. A cassette as recited in claim 16including a plurality of ridges in each of said chambers, said ridges ineach chamber extending in length between proximate the chamber inputport and proximate the chamber output port.
 20. A cassette as recited inclaim 16 wherein each said chamber input port and said chamber outputport have essentially the same cross-section configuration as thecross-section configuration of the corresponding chamber.